Mesenchymal stromal cell apoptosis is required for their therapeutic function

Area of Science:

• Cell biology
• Immunology
• Regenerative Medicine

Background:

• Multipotent mesenchymal stromal cells (MSCs) show therapeutic potential in preclinical models.
• The precise mechanisms underlying MSC efficacy remain unclear, hindering clinical translation.
• Current understanding often focuses on secreted factors from viable MSCs.

Purpose of the Study:

• To investigate the in vivo fate of intravenously administered MSCs.
• To elucidate the role of MSC apoptosis in their therapeutic mechanisms.
• To identify the host-cellular responses mediating MSC-driven immunosuppression.

Main Methods:

• Intravenous administration of MSCs in preclinical disease models.
• Genetic deletion of apoptotic effectors BAK and BAX in MSCs.
• Analysis of MSC fate, host immune cell responses, and disease outcomes.

Main Results:

• MSCs undergo apoptosis in the lung post-intravenous administration, independent of host immune rejection.
• Blocking MSC apoptosis with BAK/BAX deletion abrogated their immunosuppressive effects.
• Efferocytosis of apoptotic MSCs by alveolar macrophages modulated metabolic and inflammatory pathways, leading to immunosuppression.

Conclusions:

• MSC therapeutic efficacy is mediated by the host's response to dying cells, not solely by viable cells.
• MSC apoptosis and subsequent efferocytosis by macrophages are critical for immunosuppression and disease amelioration.
• These findings necessitate a re-evaluation of cell-based therapy strategies, emphasizing the role of cell death and host interaction.